In humans, development of the retinal vasculature occurs in relative hypoxia in utero and is complete at the time of birth. Premature birth interrupts this process and places the premature child at risk for multiorgan damage due to a simple paradox of oxygen—oxygen is necessary to keep premature infants alive, but is toxic to premature developing tissues, including the pre-term retina.
Retinopathy of prematurity (ROP) is a retinovascular disease of premature infants characterized by neovascularization at the intersection of developed, vascularized retina and undeveloped avascular retina. ROP is the most common cause of childhood blindness, and has two phases, based on the oxygen-regulated expression of vascular endothelial growth factor (VEGF). Phase I begins at birth when the infant is placed into hyperoxia, which results in a reduction in the secretion of VEGF that is associated with oxygen-induced vascular obliteration. Phase II is a hypoxic state created by weaning of oxygen supplementation and increased retinal metabolic demand exacerbated by vessel loss from phase I. Phase II is characterized by an overexpression of growth factors, such as VEGF, in the ischemic retina, resulting in pathologic neovascularization.
Although much attention has been focused on the treatment of the angiogenic phase by VEGF and hypoxia-inducible factor 1α (HIF-1α) inhibitors, these treatments do not inhibit the destruction of retinal blood vessels. Thus, there is a need for treatments for hyperoxia-associated conditions that allow for normal retinovascular development in premature infants and inhibit the development of hypoxia-induced neovascularization and phase II of the disease.